Adjusting medication doses for patients with CKD often poses major challenges for practitioners. With the number of patients with CKD expected to grow significantly in the next 20 years, experts from around the world met recently to discuss what is known, what is unknown, and what research and regulatory goals are necessary to provide safe care for these patients.1,2 This article updates providers on the practical dosing of medications for adult patients with CKD.
Before 1998, there was no FDA requirement for testing medications in patients with CKD, and few medications were tested in patients with differing levels of kidney function. In May 1998, the FDA published guidance requiring medications to include renal dosing; thus, many newer medications are tested in patients with CKD using a glomerular filtration rate (GFR) calculation to correct for dosing adjustments.3 European Medicines Agency (EMA) guidelines published in 2004 require that all manufacturers test and dose-correct their medications for patients with acute kidney injury (AKI).4 However, many older, common medications used in patients with CKD have dosing algorithms that are based primarily on post-marketing case reports and are not validated in clinical trials or pharmacokinetic studies.
Patients with renal dysfunction pose several challenges (Figure 1). What dosage is too high, and how do clinicians deal with the toxic metabolite? What is the true measure of kidney function in a patient with AKI who is rapidly deteriorating? How does one account for third spacing of fluid in patients with CKD? These questions make research and calculation of renal dosing as much an art as a science.5
ASSESSING KIDNEY FUNCTION
One of the first difficulties in treating patients with CKD is measuring kidney function. The most commonly used method is the GFR, but several different equations can be used for estimating GFR. The most frequently used research equation is the Cockcroft-Gault equation, which estimates creatinine clearance but has also been used to estimate GFR.6,7 The FDA noted this equation in its guidance for pharmacokinetic studies in patients with impaired renal function, and the equation is the most commonly used one for renal dose adjustments.3 The Modification of Diet in Renal Disease (MDRD) formula was developed in 1999 for patients with known renal disease and is invalid for patients with GFR rates above 60 mL/minute.8 Several studies comparing drug dosing using Cockcroft-Gault and MDRD equations in theoretical patient cases have resulted in mixed conclusions.9–14 Neither equation has conclusively been proven to be superior. The National Kidney Disease Education Program (NKDEP) states that either equation may be used for drug dosing in patients with renal impairment. If the MDRD equation is used for large or small patients, the NKDEP recommends adjusting for body surface area.15
The newest formula is the CKD-Epidemiology Collaboration (CKD-EPI), which is reported by the two largest laboratories in the United States in mL/minute/1.73 m2 to account for body surface area. This is believed to be the most accurate estimation of GFR.15 Providers prescribing a medication with a narrow therapeutic window need to know which formula was used to calculate kidney function. For these drugs, the Kidney Disease: Improving Global Outcomes expert panel recommends using the equation that most accurately assesses renal function.2 However, for the vast majority of medications and patients, any GFR formula is acceptable.
Each class of medications has a different profile: some require maintenance for a specific time frame, some have a narrow therapeutic window, and others require a high peak. If medications are highly protein-bound and the patient's kidney disease progresses, malnutrition (which occurs in more than 30% of patients with kidney disease) can play a role in the dosing of medications.16,17 Many medications can be adjusted by decreasing the number of doses while holding the dose constant after a loading dose. This is often done for antibiotic dosing in patients with CKD.17–21 Although measuring drug concentration levels may be useful for dosing, it is not practical in the outpatient setting.
Most renal dosing guidelines do not recommend a loading dose, but this can be an effective way to give medications in patients with CKD, especially if the drug has a long half-life.2,22 If a drug is highly protein-bound, measure the patient's serum albumin and adjust the dose (usually lowering it) to correct for the lower albumin levels seen in patients with CKD, especially those with proteinuria.16,17
Common classes of diabetes medications that require dose adjustments in patients with renal impairment include sulfonylureas, biguanides (such as metformin), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and insulin.
All the second-generation sulfonylureas can be used in patients with CKD. Glyburide, which is eliminated via the renal system, is not recommended when the patient's creatinine clearance is less than 50 mL/minute because of the increased risk of hypoglycemia.19,20 Because no renal adjustment is needed for glipizide, this drug is commonly prescribed by nephrology practitioners.19,20
Metformin has been associated with an increased incidence of lactic acidosis in patients with renal impairment. Although this remains controversial, the manufacturer's package insert specifies discontinuing the drug when serum creatinine is greater than or equal to 1.5 mg/dL in men or 1.4 mg/dL in women.21,22 Because GFR and serum creatinine do not directly correlate, many practitioners will stop metformin at a GFR of 50 mL/minute to be safe.23
Use caution when prescribing the new incretin medications, DPP-4 inhibitors, and GLP-1 agonists in patients with renal impairment. Several of these medications require dose adjustments (see Table 1).24–29 Exenatide should not be used if the patient's creatinine clearance is 30 mL/minute or less.25 Liraglutide, exenatide, and sitagliptin all have documented post-marketing reports of AKI requiring dialysis.24–26 In addition, worsening of renal function has been documented in patients with CKD who take liraglutide and exenatide.24,25
Because 40% to 50% of insulin is excreted by the kidney, dose decreases are made with loss of kidney function.19 The American College of Physicians recommends decreasing doses by 25% for patients with creatinine clearances between 10 and 50 mL/minute and by 50% for patients with creatinine clearances less than 10 mL/minute.30 However, the need for dose adjustments in patients with CKD is very patient-specific and does not always lend itself to strict guidelines.19,30
Maintenance doses of penicillins, cephalosporins, and fluoroquinolones (except moxifloxacin) generally need to be reduced in patients with renal impairment. When rapid achievement of therapeutic drug levels is desired, such as in critically ill patients, consider giving a loading dose.31
A dose reduction of 50% for sulfamethoxazole-trimethoprim (SMX-TMP) is recommended for patients with creatinine clearance between 15 and 30 mL/minute; the drug is not recommended in patients with creatinine clearance less than 15 mL/minute. Nephrotoxicity has been reported in both patients with and without renal impairment necessitating these dose adjustments.32
Nitrofurantoin should be prescribed cautiously, if at all. This drug is excreted primarily by the kidneys, with little to no elimination of the drug once the patient's creatinine clearance falls below 20 mL/minute, raising the risk of drug toxicity. Because this antibiotic is primarily used to treat urinary tract infections, adequate drug levels cannot be reached in the urine. Nitrofurantoin is contraindicated if the patient's creatinine clearance is less than 60 mL/minute.33
Several other antibiotics require dose adjustments. Some are nephrotoxic, and those that are eliminated primarily by the kidneys can accumulate and pose a risk for toxicity in patients with renal impairment. Consult a drug information reference before prescribing an antibiotic in a patient with CKD.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, leading to vasoconstriction and reduced renal perfusion. Prolonged NSAID use can lead to AKI and CKD. Patients with CKD are at high risk for further decline in renal function.34 Therefore, NSAIDs should not be used in this population. Alternatives include acetaminophen, tramadol, or opioids.
Common IV pain medications requiring dose adjustments for patients with renal impairment include meperidine and morphine. Morphine may accumulate in patients with renal impairment, leading to prolonged sedation and respiratory depression. Morphine can be used safely in patients with CKD, but the dosage should be reduced 25% in patients with creatinine clearances between 10 and 50 mL/minute, and reduced 50% in patients with creatinine clearances less than 10 mL/minute.35
Avoid using meperidine in patients with CKD; however, if it must be administered, use great caution. Normeperidine, the active metabolite of meperidine, is renally eliminated and has an extended half-life that is extended even further in patients with CKD. As a result, patients with CKD are at greatly increased risk for serious adverse effects including seizures. Dose reductions for meperidine are the same as those recommended for morphine.36
Because patients with CKD have a high incidence of diabetic neuropathy, they often are prescribed medications for neuropathic pain. Gabapentin, a drug commonly used for neuropathic pain, requires dose adjustment in patients with renal impairment (Table 2). An overdose of gabapentin poses the increased risk of adverse reactions such as somnolence, dizziness, and peripheral edema.37 On the other hand, patients on hemodialysis should receive a supplemental dose after each 4-hour hemodialysis session.
The newer anticoagulants and antiplatelets offer advantages over older agents, including oral administration and less monitoring. However, many of these drugs have not been well-studied in patients with significant renal impairment. Some anticoagulants have specific recommendations for administration in patients with renal impairment (Table 3).38–48 The new antiplatelets, prasugrel and ticagrelor, do not require dose adjustments in patients with CKD, but have not been studied in patients on hemodialysis.49,50
No discussion can be complete without mentioning hemodialysis, peritoneal dialysis (PD), and the adjustments that must be made for medication dosing in patients with kidney failure. In the last 10 years, dialyzers for hemodialysis have made a generational leap forward, and almost all patients who need hemodialysis use high-flux dialyzers.51,52 These dialyzers are larger, more aggressive, and allow passage of most solutes. Most drugs are removed by hemodialysis unless highly protein-bound.
Patients on PD should be dosed as though they had a GFR of 15 mL/minute, because multiple studies have shown similar pharmacokinetics between PD and patients with a GFR of 15 mL/minute.53,54 Remember that all transplant patients (no matter which organ was transplanted) are defined as patients with CKD, and must have their medications adjusted.55
Often the pharmacy can be challenging to navigate for patients with CKD. As the patient's renal function decreases, some medications accumulate in the body leading to toxicity, some are directly toxic to the renal tubules, and some have metabolites that do both.
* Pseudoephedrine and phenylephrine in decongestants can raise BP to dangerous levels in patients with CKD who also have hypertension.
* NSAIDs such as ibuprofen and naproxen are found in many cold medications, and can reduce renal perfusion. Headache powders, which typically contain aspirin, are nephrotoxic.
* Magnesium is common in many laxatives, such as milk of magnesia and magnesium citrate, and poses a toxicity risk in patients with CKD.
* Bismuth may be found in remedies for upset stomach, and may be toxic to the renal tubules.
* Phosphorus-containing enemas have been known to cause AKI in patients with CKD .56
* Aluminum, found in many gastrointestinal (GI) preparations, can cause bone toxicity in patients with CKD. Patients also should check if their water supplier uses aluminum in the reservoir water to settle dissolved dirt.
* Sodium bicarbonate may be found in GI preparations and cold medicines, and can cause metabolic alkalosis in patients with CKD.
* Proton-pump inhibitors have been shown to cause renal failure in patients with CKD.57
* Ranitidine and cimetidine are potent CYP450 inhibitors (cimetidine more so than ranitidine) and interfere with metabolism of many of the medications prescribed for patients with CKD. Due to competition for binding sites in the kidney, cimetidine can produce a falsely high serum creatinine reading. A patient on cimetidine must be off the drug for 72 hours before a valid GFR can be calculated.
* Calcium-based reflux medications can cause an overdose of calcium in patients with CKD and can increase the calcification of peripheral vessels. High-dose vitamin D and calcium can increase the chance of kidney stones in susceptible patients with CKD.
* Potassium in salt substitutes can lead to hyperkalemia, which can be severe in patients with CKD who also take an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
* Herbal remedies and dietary supplements can cause problems for patients with CKD and must be used with caution. Some of the herbals known to be problematic for patients with CKD include St. John's wort, echinacea, creatine, ginkgo, garlic, ginseng, ginger, and blue cohosh. Herbal remedies are especially worrisome for patients who have had transplants, because of the risk of losing the transplanted organ due to a drug interaction.
Encourage patients with CKD to talk to their pharmacist or primary care provider before taking any OTC medications.
Medications approved by the FDA before 1998 rarely have renal dosing adjustments in their prescribing information. Newer medications may provide some renal adjustments, but often these are inadequate. To help fill the gap, the kidney community is reaching out to educate other practitioners about renal medication dosing and the inherent dangers for patients with AKI and CKD.
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